Stronger Oversight of Medical Devices:
FDA Preliminary Reports and Recommendations on the 510(k) Process
A version of this article appears on the Business Leader Post.
Each year the U.S. Food and Drug Administration ("FDA")
receives over four thousand applications are submitted for approval of
medical devices. For thirty years, under the U.S. Food and Drug
Cosmetic Act ("F.D.C.A."), medical device manufacturers have been
required to demonstrate to the FDA that new medical devices are safe
and effective. The Medical Device Amendments of 1976 established a
regulatory framework for regulation of medical devices. Devices that
pose the most significant risk and scientific uncertainty must go
through the most comprehensive testing. At the risk of
oversimplification through the 510(k) process, it should be said that
devices are permitted onto the market if they are "substantially
equivalent" to devices already marketed. New devices are classified by
comparing them to devices in commercial distribution to determine if
those devices are substantially equivalent. Hence, the statutory
scheme for approval builds on existing approved devices. One
knowledgeable trade association observer has commented that "all
legislation subsequent to the Medical Device Amendments of 1976 is
built into the original statutory foundation".1
The FDA has been charged with carrying out its safety oversight
responsibilities in a way which fosters innovation so that devices are
neither over regulated nor under regulated. However, concerns have
been raised, both internally and externally, as to whether the FDA has
been reaching its goals. Consumer groups have complained in the wake
of firestorm over approval of the ReGen Biologies knee device that
political influence should have no place in the FDA review process.
Other industry stake holders have suggested that FDA reviewers "post
ReGen" have become overly restrictive in their reviews and that the
process has become "frozen". Mark Leahey, the respected President of
the Medical Device Manufacturers Association commented: "some companies
are even forgoing the U.S. market and launching outside the U.S. with
no intention of commercializing here until the environment improves".
Editorial, "FDA Reviews the 510(k) Process; An overview a dated June
2010" Orthoknow. In response to the increased criticism of the
medical device review process, the Director of the FDA's Center for
Devices and Radiological Health ("CDRH"), Dr. Jeffrey Shuren,
established internal working groups to examine the Section 510(k)
process. (Note: the CDRH is the center within the FDA responsible to
ensure that medical devices are safe and effective.) CDRH's activities
include regulatory review of product evaluation, manufacturing and
Preliminary Reports Released
On August 3, 2010 the FDA released for public comment
two long awaited reports from the internal FDA working groups on
improving the FDA's medical device pre-market review process. The FDA
released a 119 page report from the FDA's Center for Devices and
Radiological Health ("CDRH") entitled "510(k) Working Group Preliminary Report and Recommendations". The FDA also released a 51 page report from the CDRH entitled "Task Force on the Utilization of Science in Regulatory Decision Making Preliminary Report and Recommendations". 2 See CDRH Preliminary Internal Evaluations.
Both reports contain summaries of the Findings and Recommendations in
outline formats which are just a few pages long. The internal reports
were, in many respects, unusually frank and self-critical of the FDA's
501(k) process and seem to recommend increased evidentiary bases.
The current framework for the 510(k) process is a
composition of legislative, regulatory and administrative guidance.
However, the statutory language of Section 510(k) does not contain any
specific requirements as to how the FDA should review pre-market
notifications. This has drawn criticism. The 510(k) Working Group
Report acknowledged this in its Report in this regard:
"Some have asserted the [510(k)] program needs to be fundamentally re-thought – that a determination of substantial equivalence to a predicate is insufficient to provide reasonable assurance that marketed devices are safe and effective (emphasis supplied)". Report at 16.
The FDA Report also acknowledged the alternative view
of some critics that the statutory and administrative framework is
sound, but the transparency and consistency of the program's
administration needs to be improved.
The "510(k) Working Group" recommendations, if adopted,
will require Section 510 (k) submissions to contain greater
evidentiary detail with regard to demonstrating reasonable assurances
of the safety and effectiveness. The "Utilization of Science Task
Force" recommendations call for 'more complete' information about the
risks and benefits of a device. Though disagreement exists as to what
will be the final outcome of the review, there seems to be unanimity
that significant changes are underway at FDA. Though it is not possible
to address fully the lengthy Reports, this article seeks to provide an
overview of the Reports' recommendations.
The Working Groups' recommendations are sure to be
greeted by some in the medical device industry with concern that the
process will become longer and more complicated. In an August 9, 2010
article in The Gray Sheet Dr. Shuren acknowledged that comments
on the Recommendations were generally positive. Director Shuren also
noted: "by the same token, many of the comments have been tempered-some
from the industry expressing concerns about some of the
recommendations, although recognizing the devil is the details and some
on the consumer side saying we should go further than we have
Indeed, on January 19, 2011, the FDA announced a Plan of
Implementation by which twenty-five steps will be taken to implement a
so called smarter and more effective 510(k) Program. See Plan of Action for Implementation of 510(k) and Science Recommendations (PDF - 130KB)
While an additional report from the Institute of
Medicine is expected to be released in the Summer 2011, and while the
FDA has stated in its report that it has not made any decision on
specific changes to pursue, industry observers expect that the core of
the Reports' Findings and Recommendations will eventually be adopted in
the form of new regulations and guidance documents.4
510(k) Working Group Evaluation of the 510(k) program
The 510(f) Working Group was actually comprised of ten
subgroups from CDRH. These included: (1) Bundling; (2) Device
Modification; (3) De Novo; (4) Indications for Use; (5) Level of
Evidence; (6) Predicates; (7) Standards; (8) Technological
Characteristics; (9) Third-Party Review; and (10) Total Product life
cycle. Each subgroup was made up of CDRH staff at various
organizational levels. CDRH also assembled a separate team to analyze
quantitative data. Public participation came in the form of public
meetings including a public meeting on February 18, 2010, and on June
22, 2010. The Report also includes public comments logged from
January 27, 2010, through March 19, 2010. A new public meeting on some
of the agenda items is scheduled to occur on April 7-8, 2011, at the
Pre-market approvals of medical devices must occur
under the Medical Device Amendments to the F.D.C.A. The Section 510(k)
process is one of two FDA pre-market review procedures for pre-market
approval. This pre-market notification procedure is often referred to
as the 510(k) process by its statutory reference. Note: The
PMA process is analogous to the New Drug Application process in that
sponsors must submit valid scientific evidences, often based on
clinical trials to establish safety. The "submitter must
demonstrate reasonable assurance of the safety and effectiveness of the
new device for its intended use", 510(k) Report at 22.
However, medical devices may be marketed without independent pre-market
approval if the FDA concludes through a review of a "Section 510(k)"
submission that a device meets the "comparative standard of
"substantial equivalence" to a predicate medical device". "Substantial
equivalence" is determined by regulation by a comparison to a medical
device that was lawfully marketed prior to 1976, or to a device that
has been cleared through the 510(k) process.
Key Findings and Recommendations
Substantial Equivalence Clarification.
The FDA acknowledged in its 510(k) Report that although the standard
for device clearance under the section 510(k) process is "substantial
equivalence" to a "predicate device", it is challenging for the FDA to
apply consistently and appropriately the standard without a clear,
coherent and reasonable explanation of key terms in the statutory
definition of "substantial equivalence". 510(k) Report at 41.
Some critics had contended that the FDA reviewers alter their
objections with each new submission to create a moving target of
objections that cannot be satisfied. Others suggest that a supervisory
review of a not substantial equivalent decision (effectively, an
administrative appeal) is not working. The 510(k) Working Group
recommended that the CDRH clarify the meaning of "substantial
equivalence" through guidance and training. The Working Group noted in
particular that there is "insufficient clarity" about what constitutes
the "same use" as the predicate device versus a new "intended use" and
clarity issues when "different technological characteristics raise
different questions of safety and effectiveness".5
Of particular significance, the Working Group acknowledged exercising
past ‘flexibility' in construing the "intended use", the lack of
clarity regarding "intended use" and "indications for use", both inside
and outside CDRH. The Working Group also acknowledged that submitters
should be permitted, as appropriate, to change labeling on devices
without such necessarily constituting a "new" "intended use". 510(k) Report at 45. The Working Group recommended that existing Guidance's be revised and consolidated.
Among the recommendations made in the reports are: the
establishment of a new class of device (subset of class II) for which
clinical and/or manufacturing information would typically be necessary
to support a substantial equivalence determination; the disallowing of
certain predicates; changes to the concept of "intended use" of a
device; streamlining the de novo 510(k) approval process and
improvements to the 510(k) data base and notice to the industry.
Where Do We Go From Here?
Though the FDA emphasizes that no formal decisions or
timetables have been made and that the FDA is soliciting public input
on these recommendations, past history advises that stakeholders ought
to plan as if the key recommendations are likely to be adopted. The
FDA will of course access public comment and consider the Institute of
Medicine's ("IOM") independent study of Section 510 (k) scheduled to
be released in the Summer, 2011. Some have suggested that the FDA has
left many tough decisions to the IOM. It seems prudent however given
the breadth of FDA's input (from ten internal subgroups and a variety
of internal and external sources) that submitters take seriously the
recommendations contained in the Reports. Of greatest portent, seems to be the findings and recommendations pertaining to "Substantial Equivalence".
The 510(k) Working Group recommended that those offering 510 (k)
submissions provide greater assurance that any comparison of new
devices to a predicate device should be valid and well reasoned.
Guidance documents are certain to follow in this regard as well as for
predicates that are no longer appropriate as comparisons. The gravamen
(if there is one) of the Reports seems to be that there is insufficient
clarity with respect to when a device may be marketed without
pre-market approval because of a determination that the device is
"substantially equivalent" to predicate devices that are already on the
It is not clear that those industry stakeholders who
claim that they are "frozen" and cannot encourage funding for new
initiatives are going to be pleased by the preliminary reports.
Likewise, the consumer advocates may find the preliminary reports a bit
uncertain as to the exact changes to be finally adopted. However, the
FDA points to its recent involvement with infusion pump recalls and its
intention to draft further guidance in this area as exemplifying FDA
concerns for tighter oversight. How all of this turns out for the
roughly four thousand submissions made each year remains a bit of a
mystery. It will also be interesting also to consider how all of this
fits in with the recently signed information-sharing Memorandum of
Understanding with the Centers for Medicare and Medicaid Devices. See "Memorandum
of Understanding between the United States Food and Drug
Administration and Centers for Medicare & Medicaid Services".
Future articles will also address possible linkages. We are hoping that
this comprehensive analysis will enhance regulatory predictability.
Use of Predicates
The 510(k) Working Group found that CDRH has a current
practice which allows for the use of some types of predicates that may
not be appropriate. See Section, Finding, 5.1.2 Report at page
55. The Working Group further highlighted concerns that at least
twenty five percent of the submitters were citing devices that were
cleared at least five years before the time of submission and that
eight percent of the most recent submissions cited predicates that were
submitted over ten years ago. In addition to the predicate age, the
510(k) Working Group identified that submitters sometimes cite "poorly
performing predicates" and even cite devices that have been withdrawn
from the market. Report at 56. The Working Group recommended
that the CDRH consider developing a guidance document as to when a
device should no longer be available as a predicate. The Group
recommended that the CDRH consider issuance of a regulation to define
the scope grounds and appropriate procedures to fully or partially
rescind a Section 510(k) clearance. The Working Group also found the
use of so-called split predicates was a concern. Report at 58.
"The term "split predicates" refers to a situation in which a 510(k)
submitter is attempting to split the 510(k) decision-making process by
demonstrating the new device has the same "intended use" as one
predicate and "the same technological characteristics as another
predicate". Though there are clearly differences of opinion in the FDA
on split predicates and their relative helpfulness, the FDA
acknowledges these differences have led to inconsistent treatment of
510(k) submissions. Additionally, there seems to be confusion as to
the use of so-called "split"or "multiple predicates". The Working Group
recommended that the CDRH develop a guidance document on the
appropriate use of more that one predicate and the misuse of multiple
predicates. Report at 62.
De Novo Classification Process
For devices for which there are no predicate, but whose
risks may not warrant a PMA approach, the "de novo classification
process" was established. The CDRH guidance provided in applicable
part that "in order to be places in Class I or Class II under the
evaluation of 'Automatic Class III' Designation provision a device must
first have been reviewed in connection with a 510(k) pre-market
notification" Report at 64. The longer 510(k) working Group
examined the longer time frames for 'de novo classification' and noted
understandably that one limiting factor is that CDRH conducts a full
510(k) review prior to initiating the 'de novo' process. Accordingly,
the 510(k) Working Group recommended that CDRH revise the existing
guidance to streamline the current implementation of the de novo
classification process and clarify its evidentiary expectations for de
novo requests. Report at 66. The Group encouraged pre-submission engagement between submitters and review staff.
Disclosure to FDA of all Updates
Under current FDA regulations and guidance, a
manufacturer is not required to submit a new 510(k) for a device
modification unless the modification "could significantly alter the
safety or effectiveness of the device". 21 CFR 807.81(a)(3). As a
result, the CDRH does not always have complete information about the
current functions and features of devices. Although submitters are
encouraged to submit a list of modifications, there is no requirement
to do so. According to the Report, a new 510(k) is required for even
changes which may have a positive effect. In order to address
‘unreported device modifications' which may be occurring without
adequate level of regulatory oversight, the Working Group has
recommended that CDRH revise existing guidance to "clarify what types
of modifications warrant a new 510(k) and for those modifications that
do warrant a new 510(k), what modifications are eligible for a Special
510(k). Report at 69, In this connection, the Working Group
recommended that CDRH explore the feasibility of requiring each
manufacturer to provide regular, periodic updates to the Center listing
any modifications made to a device without the submission of a new
510(k) and explaining why the modification did not require a 510(k).
"Further Definitions as to Submissions"
A 510(k) submission must, among other things, contain pursuant to 21 C.F.R. 807.87 and various FDA guidance documents6:
- Proposed labels, labeling and advertisements sufficient to
describe the device; intended use and the direction for its intended
- Photographs or Engineering Drawings
- A statement indicating the device is similar to and/or different from other products (and supporting data);
- Performance Specifications and Device Design Requirements;
- List of all patient contacting components and their respective material
Notwithstanding the FDA's guidance, the 510(k) Working
Group noted that the quality and clarity of the 510(k)s vary. They
note that the information is often summarized and inadequate in its
level of detail. The Working Group have recommended that CDRH consider
adopting and "assurance case" framework for 510(k) submissions by
which submitters formally demonstrate the validity of a claim. The CDRH
would develop a guidance to reiterate "longstanding expectations" that
submissions should describe any modifications made to a device since
its previous clearance. CDRH would provide training for FDA reviewers
and managers on how to evaluate assurance cases. Report at 71.
The Working Group has recommended that detailed photographs and
schematics be provided which might be added to the public database to
the extent not containing proprietary information. At least one unit of
the devise would be available for FDA review. CDRH would also
provide additional guidance and training for submitters and review staff
regarding the appropriate use or recognized consensus standards on the
evaluation of device safety and effectiveness. Report at 72.
To address the possibility of incomplete information, the Working Group
has recommended revising 21 C.F.R. 807.87 to explicitly require 510(k)
submitters to provide "a list and brief description of all scientific
information regarding the safety and/or effectiveness of a new device
know or that should be reasonably known to the submitter." Report at 74.
Type and Level of Evidence
Though many 510(k) submissions include some bench and
animal data, the Working Group has recognized a key review challenge to
be determining when other types of information may be necessary to
support a substantial equivalence determination. The Working Group
candidly acknowledged that the CDRH may lack familiarity with
particular device types of technology. Given that certain device
submissions are commonly associated with data needs, the Working Group
has suggested that a guidance "defining a subset of Class II devices,
called "class IIb" devices for which clinical information,
manufacturing information, or potentially, additional evaluation in the
post-market setting, would typically be necessary to support a
substantial equivalence determination" Report at 76.
Industry observers are guardedly optimistic that the
January 19, 2011 Plan of Action, if implemented successfully, will
clarify and streamline the regulation development process. As
Director Sherun noted: "the new actions we are announcing will
strengthen our most commonly used pathway to market for medical
devices, called the 501(k) Program." Lets hope that the innovation
and safety goals are realized.
Robert J. Kerwin, Esq.
has served as general counsel to the International Association of
Medical Equipment Remarketers and Services, Inc. for seventeen years,
and is a shareholder in the Boston firm of Tarlow, Breed, Hart &
Rodgers, P.C. Comments concerning the article may be sent to firstname.lastname@example.org or to speak with Rob (617) 218-2039.
"The 510(k) process: The Key to Effective Device Regulation", Advanced
Medical Technology Association (AdvaMed") White Paper at page 8.
The full titles are respectively identified as "CDRH Preliminary
Internal Evaluations – Volume I-510(k) Working Group Report and
Recommendations; and "CDRH Preliminary Internal Evaluations - Volume II
Task Force on the Utilization of Science in Regulatory Decision Making
Preliminary Reported Recommendations.
On December 8, 2010 thirteen US Senators issued letter to the FDA
calling on the FDA to streamline the process and urging it to reform.
4 The last extensive FDA guidance document in this area was released in 1998.
5 See 21 C.F.R. 801.4 and 21 C.F.R. 814.20(b)(3)(i).
6 Guidance for Industry and FDA staff: Format for Traditional and Abbreviated 510(k)s (August 12, 2005)